Rehabilitation for chronic pain involves a structured treatment plan targeting all dimensions of the pain experience, and should include a comprehensive interdisciplinary approach that allows patients to receive the most benefit according to their needs. As in other chronic pain syndromes, chronic Phantom limb pain (PLP) is often difficult to treat, showing to be resistant to classical pharmacological and surgical treatment approaches. This lack of efficacy in treatment of PLP is because current rehabilitative measures do not take into account the complex underlying neural mechanisms related to this pain. In fact, extensive evidence indicates that chronic PLP is a phenomenon related to a significant reorganization of the somatosensory and motor cortex. Analgesic drugs do not counteract the mechanisms that lead to maladaptive plasticity of these areas, and therefore is not the most efficacious treatment. In this context, we hypothesize that novel treatments of PLP need to target specific neural networks associated with this maladaptive plasticity. Transcranial direct current stimulation (tDCS) is a powerful and non-invasive technique of brain stimulation that is known to significantly modulate plasticity and alleviate chronic pain in various syndromes. Recently, we showed that anodal tDCS can induce a selective short-lasting relief from PLP, and repeated applications of anodal tDCS induces long- lasting analgesic effects. These preliminary results show that tDCS may be a promising rehabilitative tool for the management of chronic PLP. Given tDCS underlying neural mechanisms, it is critical to use a multimodal approach to treatment - using both tDCS and behavioral therapy simultaneously. In this case, an ideal therapy is mirror therapy (MT). This neurorehabilitation technique is commonly used in PLP, and is designed to modulate cortical mechanisms of pain by performing movements using the unaffected limb in front of a mirror. We propose to carry out a mechanistic, factorial, randomized controlled trial to evaluate a novel rehabilitation approach combining tDCS and MT in PLP patients. We aim to compare the brain changes before and after treatment in order to study the mechanisms underlying PLP. Aim 1 will evaluate the efficacy of tDCS and MT as rehabilitative tools. Patients will be assigned to one of four groups: active tDCS/MT; sham tDCS/MT; active tDCS/sham MT (covered MT); and sham tDCS/sham MT (covered MT). Aim 2 will examine the mechanisms underlying PLP. We will use single and paired-pulse transcranial magnetic stimulation (TMS) to assess cortical mapping and cortical excitability changes associated with cortical reorganization. We will also use functional magnetic resonance imaging (fMRI) to assess brain responses in the sensory-motor cortex associated with this treatment. This proposal has a great significance as it will help to understand and develop a novel intervention for PLP. Spaulding Rehabilitation Hospital - where this proposal is being developed - is a major center for rehabilitation of amputees including most of the amputees from the Boston Marathon Bombing. RELEVANCE: Chronic phantom limb pain (PLP) is recognized as very difficult to treat as it is often resistant to classical pharmacological and surgical treatment approaches. It is a major cause of disability and a main contributor to the quality of life. Extensive evidence indicates tha PLP is a phenomenon related to significant maladaptive brain changes. In this study we propose to investigate a novel rehabilitation approach combining a behavioral therapy- mirror therapy- with a method of brain modulation (tDCS) to treat and investigate the mechanisms of PLP.